Adolescence is a developmental stage in humans that is characterized by dramatic changes in an individual's biology and their behavior. It is also a period during which individuals may begin using psychostimulant drugs, whether for therapeutic or recreational purposes. Repeated exposure to these drugs is associated with deficits in memory, decision making, impulse control, and reward processing, and these adverse consequences on cognition may persist through extended periods of drug abstinence. Thus, it is critically important to understand the neurobiological processes that mediate drug-induced changes in behavior and to determine how adolescents, compared to adults, are particularly vulnerable. Our long-term goal in these studies is to understand the neuroadaptations induced by amphetamine in corticolimbic regions of the adolescent brain and determine how these changes can be prevented or reversed. In the proposed studies, we will use behavioral, pharmacological, and electrophysiological techniques in animal models of adolescence and adulthood to address two aims. In Aim 1, we will determine if changes in dopamine and NMDA receptor function in the mPFC are responsible for the enduring deficits in cognitive behavior induced by amphetamine exposure during adolescence. In Aim 2, we will determine the basis of the long-lasting functional changes in mPFC neurons that are observed in adolescent- compared to adult-exposed individuals. Our working hypotheses are that, 1) adolescent-exposed rats, when tested as adults, will be more sensitive to drug-induced deficits in cognitive function and to selective manipulations of dopamine and NMDA receptors, compared to those exposed as adults; 2) the effects of repeated amphetamine treatment on the intrinsic firing properties, NMDA-dependent long term potentiation, and dopamine receptor-mediated responses of mPFC neurons are enhanced in adolescent- compared to adult-exposed individuals; and 3) the effects of this exposure on the in vivo responses of mPFC neurons to amphetamine and dopamine or NMDA receptor selective drugs will be greater in adolescent- compared to adult-exposed individuals. These hypotheses are consistent with our preliminary studies, which show that that exposure to amphetamine during adolescence impairs behavior on an mPFC-sensitive working memory task and alters the intrinsic firing properties of layer V pyramidal cells recorded in vitro. Through the research proposed in this application, we seek to fill the large gaps in our knowledge about what makes the brain and behavior of adolescence so uniquely different from adults and increases their vulnerability to the adverse consequences of repeated drug exposure. By understanding the unique plasticity of the adolescent brain, we will likely identify targets for preventative or therapeutic strategies aimed at ameliorating the adverse consequences of repeated amphetamine exposure during adolescence. In addition, we anticipate our results will move the field towards a clearer understanding of the unique effects of psychostimulants during this critical period of neural and behavioral development. PUBLIC HEALTH RELEVANCE: The results of these experiments in animal models will help clarify the neurobiological underpinnings of the heightened vulnerability of adolescents to the detrimental consequences of amphetamine exposure. By understanding the unique neural and behavioral processes of adolescence, neuroscience we will be able to make significant advances in our attempts to more effectively prevent and treat the behavioral adaptations, including cognitive deficits, that result from drug exposure early in life.